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WO2022187280A1 - Redirection et reprogrammation personnalisées de lymphocytes t pour un ciblage précis de tumeurs - Google Patents

Redirection et reprogrammation personnalisées de lymphocytes t pour un ciblage précis de tumeurs Download PDF

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Publication number
WO2022187280A1
WO2022187280A1 PCT/US2022/018389 US2022018389W WO2022187280A1 WO 2022187280 A1 WO2022187280 A1 WO 2022187280A1 US 2022018389 W US2022018389 W US 2022018389W WO 2022187280 A1 WO2022187280 A1 WO 2022187280A1
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Prior art keywords
cells
cell
tcf7
gene
inhibitor
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PCT/US2022/018389
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English (en)
Inventor
Marc Schwartz
Nir Hacohen
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Dana-Farber Cancer Institute, Inc.
The General Hospital Corporation
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Publication date
Application filed by Dana-Farber Cancer Institute, Inc., The General Hospital Corporation filed Critical Dana-Farber Cancer Institute, Inc.
Priority to US18/279,848 priority Critical patent/US20240150711A1/en
Publication of WO2022187280A1 publication Critical patent/WO2022187280A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7156—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases RNAses, DNAses
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPRs]
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/50—Cell markers; Cell surface determinants
    • C12N2501/515—CD3, T-cell receptor complex
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/60—Transcription factors
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/65—MicroRNA
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/70—Enzymes
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    • C12N2501/727—Kinases (EC 2.7.)
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15042—Use of virus, viral particle or viral elements as a vector virus or viral particle as vehicle, e.g. encapsulating small organic molecule
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present disclosure also provides methods of treatment of a subject by isolating T cells, modifying (or reprogamming) the T cells ex vivo , and administering the modified cells to the subject.
  • modifying the T cells comprises modulation of the expression of TCF7 in the cells, such as increasing TCF7 expression.
  • Isolated T cells may be isolated from the subject.
  • the T cells may be further modified ex vivo through the genetic modification (or grafting) of one or more T cell receptors (TCRs) expressed by these T cells, such as TCRs possessing confirmed tumor-reactivity.
  • TCRs T cell receptors
  • the inhibitor is ruxolitinib, baricitinib, fedratinib, gandotinib, lestaurtinib, momelotinib, pacritinib, pravastatin, ISS-840, fludarabine, OPB-31121, or heparin.
  • the candidate modulator gene is a gene that encodes a transcription factor.
  • the candidate modulator gene is a gene that encodes a Kriippel associated box (KRAB) domain.
  • KRAB domains are transcriptional repression domains present in many zinc-finger proteins, such as zinc-finger nucleases (ZFNs).
  • kits for the preparation of a medicament of modified T cells are provided herein.
  • FIG. 11 is a schematic showing experimental method to evaluate the effect of blocking Ifn- gamma signaling in CD8+ T cells using a separate method from CRISPR-deletion.
  • FIG. 12 shows bar graphs showing the fraction of cells in each well that were positive for Tcf7 protein expression at day 5, day 7, day 8, and day 11 post stimulation in all conditions.
  • FIG. 14 is a schematic showing a general experimental setup for in vivo phenotyping experiments for inhibition of Ifngrl .
  • the candidate modulator gene is a negative modulator of TCF7. In some embodiments, the candidate modulator gene is a positive modulator of TCF7.
  • the candidate modulator gene may be selected from the following genes: Ac lb, Hifla, Ndufs2, Samdl, Aplml, Hira, Nelfb, Slc2al, Arhgapl, Flnrnpab, Pabpcl, Slc35a2, Arnt, I FN-vR I ( Ifngrl ), Pgd, Slc7al, Atxn7l3, I FN-vR2 ( Ifngr2 ), Pgkl, Slc7a5, Bapl, Il21r, Pgm3, Smarca4, Brd4, Il2ra, Phip, Smarcel, Ccdc6, Ints5, Pik3cd, Socs3, Chd4, lnts6, Pik3cg, Spcs2, Cited2, I
  • the term “candidate modulator gene” refers to a gene that has not been previously identified as a negative modulator gene (e.g., modulator of TCF7 expression) but is subject to a screen that may subsequently identify it as a negative modulator gene.
  • Candidate modulator genes are typically not known by the experimenter a priori to be negative modulator genes.
  • adoptive transfer therapies are contemplated herein.
  • methods of treatment comprise isolating T cells from a subject, contacting ex vivo the naive T cells of a subject using any of the methods of preparing a modified T cells described herein, and infusing the modified T cells into the same subject or another subject. This type of treatment is referred to herein as an adoptive transfer therapy.
  • Adoptive transfer therapies of the disclosure may be autologous or allogeneic.
  • the T cells obtained by the inventive methods can be used in methods of treating or preventing cancer.
  • the invention provides a method of treating or preventing cancer in a subject, comprising administering to the subject the pharmaceutical compositions or cell populations obtained by any of the methods described herein in an amount effective to treat or prevent cancer in the subject.
  • Another embodiment of the invention provides a method of treating or preventing cancer in a subject, comprising administering a cell population enriched for tumor-reactive T cells to a subject by any of the inventive methods described herein in an amount effective to treat or prevent cancer in the mammal.
  • inventive methods can provide any amount or any level of treatment or prevention of cancer in a mammal.
  • the treatment or prevention provided by the inventive method can include treatment or prevention of one or more conditions or symptoms of the disease, e.g., cancer, being treated or prevented. Also, for purposes herein, “prevention” can encompass delaying the onset of the disease, or a symptom or condition thereof.
  • lentiviral transduction method P14 T cells were transferred to mice infected with acute lymphocytic choriomeningitis virus (FCMV), Armstrong strain. T cells were transduced, 5 days later transferred to recipient mice that were then infected with FCMV. Cells were analyzed at 7 and 30 days. The results shown in FIG. 3 A indicate that transduced T cells expand and contract in line with co-transferred fresh naive cells, maintaining the same cell number ratio and adopting the same effector and memory phenotypes.
  • FCMV acute lymphocytic choriomeningitis virus
  • Step 2 Virus Titer
  • Example 2 Effects of inhibition of IFN-gamma receptor on TCF7 expression and T cell persistence in vivo
  • Naive CD8 T cells that received either control or Ifngrl -targeting sgRNAs were co-cultured with MC38-OVA tumor cells, and two days later the number of live tumor cells and the viability of T cells was quantified, as shown in FIG. 10.
  • the MC38-OVA line expresses ovalbumin.
  • Experimental wells contained T cells at effector: target (E:T) ratios of 1:10, 1:5, and 1:2. Ifngrl -deficient CD8s were able to kill tumor cells at all tested E:T ratios, although tumor killing was somehwat less efficient at lower E:T ratios. As shown in the right panel of FIG. 10, at higher E:T ratios, a superior survival of Ifngrl -deficient T cells is observed.
  • CD8 T cells were isolated from WT mice and treated with isotype or a combination of anti-Ifng and anti-IfngR neutralizing antibodies.
  • Cells were stimulated with anti-CD3/anti-CD28 antibodies and cultured for 1 week in a mixture of recombinant interleukins: IL-2, IL-7, IL-15, and IL-21.
  • Cells were then co-cultured with MC38-OVA tumor cells at various E:T ratios, and tumor cell cytotoxicity was subsequently measured.
  • FIG. 21 there were 8 recipient mice that completely cleared their tumors, and those mice were immunized with OVA-CpG 50 days after T cell transfer. Eight days after vaccination, spleens and lymph nodes were harvested to quantify the number of transferred OT1 T cells that persisted. As shown in FIGs. 22A-22B, the use of congenic markers CD45.1 and CD45.2, transferred OT1 cells were only detected in mice that received Ifngrl-sgRNA containing CD8 T cells.
  • Table 1 [00159] Table 2, below, shows 239 candidate modulator genes, which include the 170 unique genes listed in Table 1, that have p values below 10 3 , which is used as a criterion for additional screens and validation experiments.
  • the numbers in the column to the left of each gene represent the log fold change: if the number is positive the gene is a possible negative regulator of Tcf7, while if the number is negative the gene is a possible positive regulator of Tcf7.

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Abstract

La présente invention concerne des procédés de reprogrammation des lymphocytes T polyclonaux pour maintenir une persistance à long terme. La présente invention concerne également des méthodes de traitement, tels que les thérapies adoptives de transfert de lymphocytes T, exploitant les lymphocytes T à mémoire centrale (Tscm) pour le développement de lymphocytes T réactifs aux tumeurs. Dans certains modes de réalisation, la présente invention fournit des procédés et des compositions pour la modulation positive du phénotype producteur de Tscm, par exemple, la modulation positive de l'expression de TCF7. La modulation positive de l'expression de TCF7 permet le maintien d'un nombre accru de lymphocytes T de type souche capables à la fois de s'auto-renouveler et de générer une progéniture différenciée et cytolytique.
PCT/US2022/018389 2021-03-01 2022-03-01 Redirection et reprogrammation personnalisées de lymphocytes t pour un ciblage précis de tumeurs WO2022187280A1 (fr)

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Publication number Priority date Publication date Assignee Title
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US5443983A (en) 1986-08-08 1995-08-22 Regents Of The University Of Minnesota Method of culturing lymphocytes and method of treatment using such lymphocytes
US5126132A (en) 1989-08-21 1992-06-30 The United States Of America As Represented By The Department Of Health And Human Services Tumor infiltrating lymphocytes as a treatment modality for human cancer
US6251385B1 (en) 1989-10-03 2001-06-26 David S. Terman Method of cancer treatment
US5846827A (en) 1993-08-06 1998-12-08 Cytel Corporation Methods for ex vivo therapy using peptide-loaded antigen presenting cells for the activation of CTL
US6040177A (en) 1994-08-31 2000-03-21 Fred Hutchinson Cancer Research Center High efficiency transduction of T lymphocytes using rapid expansion methods ("REM")
US6255073B1 (en) 1995-03-08 2001-07-03 The Scripps Research Institute Antigen presenting system and methods for activation of T-cells
US6194207B1 (en) 1997-01-31 2001-02-27 Hemosol Inc. Methods for the selective expansion of lymphocytes by in vitro cultivation
WO2003020763A2 (fr) 2001-08-31 2003-03-13 Avidex Limited Substances
WO2004033685A1 (fr) 2002-10-09 2004-04-22 Avidex Ltd Recepteurs de lymphocytes t de recombinaison a chaine unique
WO2004044004A2 (fr) 2002-11-09 2004-05-27 Avidex Limited Presentation de recepteurs pour l'antigene des lymphocytes t
WO2004074322A1 (fr) 2003-02-22 2004-09-02 Avidex Ltd Recepteur des lymphocytes t soluble modifie
WO2005114215A2 (fr) 2004-05-19 2005-12-01 Avidex Ltd Procede d'amelioration des recepteurs des lymphocytes t (trc)
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